Part I – HER2-Positive Breast Cancer Thursday, June 21, :30 PM – 8:30 PM ET RTP TV: A Live CME Webcast Series on Novel Treatments in Oncology

Kimberly L Blackwell, MD Professor of Medicine Director, Breast Cancer Program Duke Cancer Institute Durham, North Carolina Mark D Pegram, MD Director, Breast Oncology Program Co-Director, Experimental Therapeutics Program Professor of Medicine Stanford University Medical Center Stanford, California Neil Love, MD Research To Practice Miami, Florida

Agenda - HER2-Positive Breast Cancer Pertuzumab –CLEOPATRA trial results –Current clinical implications T-DM1 (Trastuzumab Emtansine) –EMILIA trial results –Future clinical implications Adjuvant/Neoadjuvant Treatment –Use of anthracyclines –Ongoing trials Audience Questions and Cases

Dr Pegram (Case 1) April 2012: 39-year-old woman with a T1 ER/PR-positive, HER2-positive IDC –CT scan done for a clinical trial showed a solitary liver metastasis –Biopsy compatible with primary

What would be your immediate treatment strategy?

What initial anti-HER2 treatment would you recommend?

Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer Baselga J et al. N Engl J Med 2012;366(2): Cardiac Tolerability of Pertuzumab plus Trastuzumab plus Docetaxel in Patients with HER2-Positive Metastatic Breast Cancer in the CLEOPATRA Study Ewer M et al. Proc ASCO 2012;Abstract 533.

Pertuzumab and Trastuzumab: Complementary Mechanisms of Action HER1/3/4 Pertuzumab HER2 Trastuzumab Subdomain IV Dimerization domain Trastuzumab: Inhibits ligand-independent HER2 signaling Activates ADCC Prevents HER2 ECD shedding Pertuzumab: Inhibits ligand-dependent HER2 dimerization and signaling Activates ADCC ADCC = antibody-dependent cell-mediated cytotoxicity; ECD = extracellular domain

CLEOPATRA Study Design Baselga J et al. N Engl J Med 2012;366(2): Centrally confirmed HER2- positive locally recurrent, unresectable or metastatic BC (mBC) ≤1 hormonal regimen for mBC Prior (neo)adjuvant systemic rx, incl trastuzumab and/or taxane allowed if followed by DFS ≥12 mo Baseline LVEF ≥ 50%; no CHF or LVEF < 50% during or after prior trastuzumab Trastuzumab Docetaxel (≥6 cycles recommended) Trastuzumab Docetaxel (≥6 cycles recommended) Placebo Pertuzumab 1:1 N = 406 N = 402 R Primary endpoint: Independently assessed progression-free survival

Baselga J et al. N Engl J Med 2012;366(2): CLEOPATRA: Progression-Free Survival Independently assessed Pertuzumab (n = 402) Control (n = 406)HRp-value Median PFS18.5 mo12.4 mo0.62<0.001

Baselga J et al. N Engl J Med 2012;366(2): CLEOPATRA: Overall Survival (Interim Analysis) Pertuzumab (n = 402) Placebo (n = 406)HRp-value Deaths*17.2%23.6% *Did not meet the O’Brien-Fleming stopping boundary of the Lan-DeMets alpha spending function for this interim analysis of overall survival and was therefore not significant.

Select adverse events (Grade ≥3) Pertuzumab (n = 407) Placebo (n = 397) Neutropenia48.9%45.8% Febrile neutropenia13.8%7.6% Leukopenia12.3%14.6% Diarrhea7.9%5.0% Peripheral neuropathy2.7%1.8% Left ventricular systolic dysfunction1.2%2.8% Baselga J et al. N Engl J Med 2012;366(2): CLEOPATRA: Safety Results

PertuzumabPlacebo LVSD (any grade) (n = 407, 397) 4.4%8.3% Symptomatic LVSD (Grade ≥3) (n = 407, 397) 1.0%1.8% LVEF decline to <50% and by ≥10% points from baseline (n = 393, 379) 3.8%6.6% Ewer M et al. Proc ASCO 2012;Abstract 533. LVSD = left ventricular systolic dysfunction; LVEF = left ventricular ejection fraction CLEOPATRA: Cardiac Tolerability of Pertuzumab plus Trastuzumab plus Docetaxel in Patients with HER2-Positive mBC

FDA Press Release on Pertuzumab June 11, 2012 The US Food and Drug Administration approved pertuzumab, a new anti-HER2 therapy, to treat patients with HER2-positive metastatic breast cancer. This agent is intended for patients who have not received prior treatment for metastatic breast cancer with an anti-HER2 therapy or chemotherapy. Pertuzumab is approved for administration in combination with trastuzumab and docetaxel.

Pertuzumab Monotherapy After Trastuzumab-Based Treatment and Subsequent Reintroduction of Trastuzumab: Activity and Tolerability in Patients with Advanced Human Epidermal Growth Factor Receptor 2- Positive Breast Cancer Cortes J et al. J Clin Oncol 2012;30(14):

Pertuzumab Monotherapy After Trastuzumab-Based Treatment and Subsequent Reintroduction of Trastuzumab HER2+ mBC progressing on trastuzumab + chemotherapy (N = 29) HER2+ mBC progressing on trastuzumab + chemotherapy (N = 29) Cortes J et al. J Clin Oncol 2012;30(14):  Pertuzumab ORR = 3.4% Pertuzumab ORR = 3.4% Pertuzumab + trastuzumab (n = 17) ORR = 17.6% Pertuzumab + trastuzumab (n = 17) ORR = 17.6% 

Krop IE. J Clin Oncol 2012;30(14): Doubling Down on Human Epidermal Growth Factor Receptor 2 “These results are consistent with the hypothesis that the two antibodies together are more effective than pertuzumab monotherapy. However, on their own, these data are not definitive. The study is limited by the extremely small sample size and the possibility that selection bias influenced which of the patients went on to receive the combination therapy.”

Dr Blackwell (Case 2) A 54-year-old woman presented in January 2010 with ER/PR-negative, HER2-positive (IHC 3+, FISH+) inflammatory breast cancer CT-confirmed metastases to the liver, bone and mediastinum May 2010: Enrolled on CLEOPATRA trial –Docetaxel dose reduction after 2 cycles due to papular rash Docetaxel discontinued after 6 cycles Remains on antibody therapy alone Patient is doing well with no study-related toxicities

Are there currently patients in your practice who have received anti-HER2 treatment for metastatic breast cancer for whom you would consider pertuzumab?

Consider the last patient in your practice who died of HER2-positive metastatic breast cancer. How many lines of systemic treatment did the patient receive?

Line of CTTotal N% receiving CT Median duration of CT %9.0 mo 24476%5.1 mo 34069%6.3 mo 43052%4.7 mo 52440%4.0 mo 61933%4.2 mo Seah DS et al. Proc ASCO 2012;Abstract Percentage of Patients with HER+ mBC Receiving n th Line of Chemotherapy (CT) and Duration of CT by Line of Treatment Retrospective Medical Record Review of 207 Women at DFCI

Dr Blackwell (Case 3) A 51-year-old woman presents with ER-positive, HER2-positive, widely metastatic disease in December 2008 January - April 2009: Paclitaxel/carboplatin/ trastuzumab June January 2011: Tamoxifen/trastuzumab In January 2011 developed shortness of breath due to pericardial effusion; cytology consistent with breast primary CT scan showed extensive metastases including pleural progression March 2011: Enrolled on EMILIA trial and randomly assigned to T-DM1

Adapted from Mackey JR. Discussant, ASCO 2009 Metastatic Breast Cancer Poster Discussion. DM1 is a highly potent antimicrotubule agent T-DM1 undergoes receptor-mediated internalization Free DM1 is released within the cell Trastuzumab-DM1 Trastuzumab HER2 Nucleus Trastuzumab-DM1 (T-DM1)

Primary Results from EMILIA, a Phase III Study of Trastuzumab Emtansine (T-DM1) versus Capecitabine (X) and Lapatinib (L) in HER2-Positive Locally Advanced or Metastatic Breast Cancer (MBC) Previously Treated with Trastuzumab (T) and a Taxane Blackwell KL et al. Proc ASCO 2012;Abstract LBA1.

EMILIA Study Design Blackwell K et al. Proc ASCO 2012;Abstract LBA1. Centrally confirmed HER2+ LABC or mBC (N = 980) Prior taxane and trastuzumab Progression on metastatic treatment or within 6 months of adjuvant treatment T-DM1 3.6 mg/kg q3wk IV T-DM1 3.6 mg/kg q3wk IV Capecitabine 1,000 mg/m 2 orally BID d1-14, q3wk + lapatinib 1,250 mg/day orally qd 1:1 R Primary endpoints: Independently assessed progression-free survival, overall survival and safety PD

With permission from Blackwell KL et al. Proc ASCO 2012;Abstract LBA1. EMILIA: Progression-Free Survival by Independent Review Median (mo) No. events Cape + Lap (n = 496) T-DM1 (n = 495) HR = (95% CI, 0.549, 0.771); p = Unstratified HR = (p = <0.001) Time (months) Proportion progression-free

With permission from Blackwell KL et al. Proc ASCO 2012;Abstract LBA1. EMILIA: Overall Survival (Interim Analysis) Median (mo)No. events Cape + Lap T-DM1NR94 Stratified HR = (95% CI, 0.48, 0.81); p = Efficacy stopping boundary p = or HR = Time (months) Proportion surviving 77.0% 47.5% 65.4% 84.7%

Select adverse events (Grade ≥3) T-DM1 (n = 490) Cape + Lap (n = 488) Diarrhea1.6%20.7% Hand-foot syndrome0%16.4% Vomiting0.8%4.5% Nausea0.8%2.5% Mucosal inflammation0.2%2.3% Increased AST4.3%0.8% Increased ALT2.9%1.4% Thrombocytopenia12.8%0.2% Blackwell KL et al. Proc ASCO 2012;Abstract LBA1. EMILIA: Adverse Events

MARIANNE: A Phase III, Randomized Study of Trastuzumab-DM1 (T-DM1) with or without Pertuzumab (P) Compared with Trastuzumab (H) plus Taxane for First-Line Treatment of HER2-Positive, Progressive, or Recurrent Locally Advanced or Metastatic Breast Cancer (MBC) Ellis PA et al. Proc ASCO 2011;Abstract TPS102.

MARIANNE: Trial Design Ellis PA et al. Proc ASCO 2011;Abstract TPS June Eligibility Histologically/cytologically confirmed breast adenocarcinoma Locally recurrent or mBC HER2 positivity Candidate for chemotherapy Measurable or nonmeasurable disease per RECIST 1.1 Adequate organ function Trastuzumab + taxane* R T-DM1 + pertuzumab T-DM1 + placebo Primary endpoint: PFS * Docetaxel or paclitaxel

Select Agents Under Investigation in HER2+ BC Afatinib Neratinib Canertinib TAK-285 BMS CP TK inhibitorsPI3K/PTEN inhibitors XL147 BKM120 mTOR inhibitors Everolimus Ridaforolimus PI3K/AKT/mTOR inhibitor BEZ235 HSP90 inhibitor Panobinostat HDAC inhibitor AUY922 IGF-1R/InsR TKI BMS Angiopoietin 1/2 inhibitor AMG 386

Dr Pegram (Case 4) A 38-year-old woman originally diagnosed with weakly ER-positive, HER2-positive, node-negative, high-grade DCIS with microinvasion in 1997 –She did not receive adjuvant chemotherapy –March 2003: Experiences local recurrence Biopsy-proven HER2-positive “Quasi-adjuvant” paclitaxel/trastuzumab –October 2008: Metastatic disease Trastuzumab/nab paclitaxel/bevacizumab on trial –February 2010: Progressive metastatic disease while on trastuzumab Enrolled on EMILIA study

HER2-Positive Early Breast Cancer (Case 5) An otherwise healthy 60-year-old woman with a 1.8-cm, ER/PR-positive, HER2-positive, Grade II IDC 1 of 3 sentinel nodes positive for disease (ALND reveals no other positive nodes)

Which treatment would you likely recommend for this patient in addition to hormonal therapy?

5% 14% 24% 57% 0% 10%20%30%40%50%60% Other Docetaxel/cyclophosphamide/ trastuzumab Paclitaxel/trastuzumab AC TH TCH (docetaxel/carboplatin/ trastuzumab)

Adjuvant Trastuzumab in HER2-Positive Breast Cancer Slamon D et al. N Engl J Med 2011;365(14):

Outcome AC  T (n = 1,073) AC  TH (n = 1,074) TCH (n = 1,075) Estimated 5-y DFS Hazard ratio p-value 75% — 84% 0.64 < % Estimated 5-y overall survival Hazard ratio p-value 87% — 92% 0.63 < % Slamon D et al. N Engl J Med 2011;365(14): DFS = disease-free survival; T = docetaxel; H = trastuzumab; TCH = docetaxel/carboplatin/trastuzumab BCIRG 006: Phase III Trial Evaluating AC  T, AC  TH and TCH in the Adjuvant Treatment of HER2-Amplified Early Breast Cancer

Select adverse events AC  T (n = 1,073) AC  TH (n = 1,074) TCH (n = 1,075) Distant breast cancer recurrence17.5%11.5%13.4% Cardiac-related death0% Congestive heart failure0.7%2.0%0.4%* >10% relative reduction in left ventricular ejection fraction 11.2%18.6%9.4% † Slamon D et al. N Engl J Med 2011;365(14): * p < for the AC  TH versus TCH † p < for the comparison between AC  TH and TCH BCIRG 006: Adverse Events

Love N et al. Patterns of Care: Breast Cancer Edition, Issue 2, years old POCI TCH62%49% AC-TH35%51% TC + trastuzumab2%0% No additional systemic therapy1%0% 60-year-old woman: 1.8-cm, ER/PR-positive, HER2-positive, Grade II IDC with 1/3 sentinel nodes positive for disease In addition to endocrine therapy, which treatment would you most likely recommend for this patient? Practicing Oncologists (PO) = 100; Clinical Investigators (CI) = 41

Schedule of Events Thursday, July 26 Colorectal Cancer Richard M Goldberg, MD Axel Grothey, MD Thursday, September 13 Renal Cell Carcinoma Thomas E Hutson, DO, PharmD Robert J Motzer, MD Thursday, October 11 Advanced Prostate Cancer Christopher J Logothetis, MD A Oliver Sartor, MD